Method for treating hepatitis c virus infection in treatment failure patients

ABSTRACT

The present invention provides methods for treating individuals having a hepatitis C virus (HCV) infection, which individuals have failed to respond to therapy with an IFN-α other than consensus interferon (CIFN), or who, following cessation of therapy with an IFN-α other than CIFN, have suffered relapse. The methods generally involve a treatment regimen comprising administering a first dosing regimen of CIFN, followed by a second dosing regimen of CIFN. Ribavirin is administered with at least the second dosing regimen.

FIELD OF THE INVENTION

This invention is in the field of treating viral infections, and inparticular, treating hepatitis C virus infection.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) infection is the most common chronic blood borneinfection in the United States. Although the numbers of new infectionshave declined, the burden of chronic infection is substantial, withCenters for Disease Control estimates of 3.9 million (1.8%) infectedpersons in the United States. Chronic liver disease is the tenth leadingcause of death among adults in the United States, and accounts forapproximately 25,000 deaths annually, or approximately 1% of all deaths.Studies indicate that 40% of chronic liver disease is HCV-related,resulting in an estimated 8,000-10,000 deaths each year. HCV-associatedend-stage liver disease is the most frequent indication for livertransplantation among adults.

The high prevalence of chronic HCV infection has important public healthimplications for the future burden of chronic liver disease in theUnited States. Data derived from the National Health and NutritionExamination Survey (NHANES III) indicate that a large increase in therate of new HCV infections occurred from the late 1960s to the early1980s, particularly among persons between 20 to 40 years of age. It isestimated that the number of persons with long-standing HCV infection of20 years or longer could more than quadruple from 1990 to 2015, from750,000 to over 3 million. The proportional increase in persons infectedfor 30 or 40 years would be even greater. Since the risk of HCV-relatedchronic liver disease is related to the duration of infection, with therisk of cirrhosis progressively increasing for persons infected forlonger than 20 years, this will result in a substantial increase incirrhosis-related morbidity and mortality among patients infectedbetween the years of 1965-1985.

Antiviral therapy of chronic hepatitis C has evolved rapidly over thelast decade, with significant improvements seen in the efficacy oftreatment. Nevertheless, even with combination therapy using pegylatedIFN-α plus ribavirin, 40% to 50% of patients fail therapy. Thesepatients are generally referred to as “treatment failure” patients, andinclude both non-responders (patients in whom viral titer remains higheven during therapy) and relapsers (patients in whom viral titers dropinitially during therapy, but subsequently rise either during therapy orafter treatment has ended). These patients currently have no effectivetherapeutic alternative. In particular, patients who have advancedfibrosis or cirrhosis on liver biopsy are at significant risk ofdeveloping complications of advanced liver disease, including ascites,jaundice, variceal bleeding, encephalopathy, and progressive liverfailure, as well as a markedly increased risk of hepatocellularcarcinoma.

Type I interferons are cytokines that exhibit both antiviral andantiproliferative activity. Type I interferons include interferon-α(IFN-α) and interferon-β. IFN-α includes naturally occurring IFN-α, andderivatives having the amino acid sequence of a naturally occurringIFN-α, such as in PEGylated IFN-α. Naturally occurring IFN-α that havebeen used in anti-viral therapies includes IFN-α2a, IFN-α2b. Derivativesof naturally occurring IFN-α, e.g., PEGylated IFN-α's, have also beenused in antiviral therapy.

Consensus IFN-α's (IFN-con; IFN alfacon; CIFN) are forms ofnon-naturally occurring type I IFN-α. Consensus interferon alphasinclude IFN-con₁, IFN-con₂, and IFN-con₃. In vitro studies comparing therelative antiviral, antiproliferative, and natural killer cellactivities of recombinant CIFN with either leukocyte or otherrecombinant type-one interferons demonstrate that CIFN displayssignificantly higher activity when compared on a mass basis. Others havereported that CIFN, when used in the treatment of diseases susceptibleto treatment by alpha interferons, does not cause the same degree ofside effects in patients as do the alpha interferons. It has also beenreported that 3 to 5 times higher doses of CIFN can be used, leading toenhanced therapeutic benefit, with substantially no correspondingincrease in the frequency or severity of undesirable side effects. Somesuccess has been reported in the use of CIFN monotherapy to treatpatients that failed to respond to IFN-α therapy.

Even in view of the therapies currently available, there remains a needfor improved therapies for treatment failure patients. The presentinvention addresses this need.

Literature

U.S. Pat. No. 5,980,884. U.S. Pat. No. 5,372,808. Aliaga, S. et al.,Farmacia Clinica (Spain) 14(5):324-331 (June 1997); Bailly, F. et al.,Nephrol. Dial. Transplant. 11(Suppl. 4):56-57 (1996); Bizollon, T. etal., Hepatol. 26:500-504 (1997); Brillanti, S. et al., J. Hepatol.23(Suppl.2):13-16 (1995); Camps, J. et al., J. Hepatol. 19:408-412(1993); Davis et al., Hepatol. 26(Suppl. 1):122S-127S (September 1997);Davis, G. L., Gastroenterol. Clin. N. Amer. 23(3):603-613 (1994);Dusheiko, G. M. et al., Br. Med. J. 312:357-364 (1996); Fried, M. W.,Med. Clin. N. Anmer. 80(5):957-972 (1996); Lindsay, K., Hepatol.26(Suppl. 1):71S-77S (September 1997); Mazzaferro, V. et al.,Transplant. Proc. 29:519-521 (1997); McHutchison, J., Hepatol.26(2):505-506 (August 1997); Merican, M. I., Med. J. Malaysia47(3):158-169 (1992); Poupon, R. and Serfaty, L., Bull. Acad. Natle.Med. 180(6):1279-1289 (1996); Reichard, O., Scand. J. Infect. Dis.(Suppl. 95):1-56 (1994); Saracco, G. and Rizzetto, M., Drugs 53(1):74-85(1997); Schalm, S. W. and Brouwer, J. T., Scand. J. Gastroenterol.223:46-49 (1997); Schalm, S. W. et al., Dig. Dis. Sci. 41(12):131S-134S(December 1996); Scotto, G. et al., Ital. J. Gastroenterol. 28:505-511(1996); Scotto, G. et al., J. Chemother. 7(1):58-61 (1995); Theodor, E.and Regev, A., Harefuah 132(6):402-403, 447 (1997); Thomas, H. C. etal., Drugs 52(Suppl. 2):1-8 (1996); Tillmann, H. and Manns, M., KidneyBlood Press. Res. 19(3-4):215-219 (1996); Tong, M. et al., J.Gastroenterol. Hepatol. 9:587-591 (1994); Trepo, C. et al., Nephrol.Dial. Transplant. 11(Suppl. 4):62-64 (1996); Weiss, R. and Oostrom-Ram,T., Vet. Microbiol. 20:255-265 (1989); Chemello, L. et al., J. Hepatol.23(Suppl. 2):8-12 (1995); Main, J., J. Hepatol. 23(Suppl. 2):32-36(1995); Schalm, S. W. et al., J. Hepatol. 26:961-966 (May 1997);Sherlock, S., J. Hepatol. 23(Suppl. 2):3-7 (1995); Braconier, J. et al.,Scand. J. Infect. Dis. 27:325-329 (1995); Brillanti, S. et al.,Gastroenterol. 107:812-817 (1994); Chemello, L. et al., J. Hepatol.21(Suppl. 1):s12 Abstract No. GS 5/29 (1994); Cohen, J., Science285:26-30 (2 Jul. 1999); Lai, M-Y. et al., Gastroenterol. 111:1307-1312(1996); McHutchison, J. G. et al., N. Eng. J. Med. 339(21):1485-1491(1998); Poynard, T. et al., The Lancet 352(9138):1426-1432 (1998;Schvarcz, R. et al., J. Hepatol. 23(Suppl. 2):17-21 (1995); andSchvarcz, R. et al., J. Med. Virol. 46(1):43-47 (1995)

Melian and Plosker (2001) Drugs 61:1-31; Heathcote et al. (1998)Hepatol. 27:1136-1143; Heathcote et al. (1999) Hepatol. 30:562-566;Sjögren et al. (Apr. 30, 2000) 35^(th) Annual Meeting of the EuropeanAssociation for the Study of the Liver Rotterdam; Chow et al. (1998)Hepatol. 27:1144-1148; Chemello et al. (1997) C. Gastroenterol.113:1654-1659; Davis et al. (1998) N. Engl. J. Med. 339:1493-1499;Kaiser et al. (Apr. 20, 2001) 36^(th) Annual Meeting of the EuropeanAssociation for the Study of the Liver, Prague; Sjögren (Apr. 20, 2001)36^(th) Annual Meeting of the European Association for the Study of theLiver, Prague.

SUMMARY OF THE INVENTION

The present invention provides methods for treating individuals having ahepatitis C virus (HCV) infection, which individuals have failed torespond to therapy with an IFN-α other than consensus interferon (CIFN),or who, following cessation of therapy with an IFN-α other than CIFN,have suffered relapse. The methods generally involve a treatment regimencomprising administering a first dosing regimen of CIFN, followed by asecond dosing regimen of CIFN. Ribavirin is administered with at leastthe second dosing regimen.

In one aspect, the invention features a method for treating a hepatitisC virus infection in an individual. The methods generally involvedelivery of CIFN and ribavirin, where CIFN is administered in atherapeutic regimen comprising a first dosing regimen of CIFN, followedby a second dosing regimen of CIFN, where the lowest average daily serumconcentration of CIFN achieved by the first dosing regimen is greaterthan the highest average daily serum concentration of CIFN achieved bythe second dosing regimen. Ribavirin is administered duringadministration of at least the last dosing event of the second dosingregimen, and may be administered with additional dosing eventscontinuous with the last dosing event during which ribavirin isadministered. The individual treated has failed previous IFN-α-basedtherapy, e.g., the individual has either failed to respond to IFN-αtherapy other than CIFN therapy, or, following cessation of IFN-αtherapy other than CIFN therapy, has suffered a relapse.

Definitions

The term “treatment failure patients” (or “treatment failures”) as usedherein generally refers to HCV-infected patients who failed to respondto previous therapy for HCV (referred to as “non-responders”) or whoinitially responded to previous therapy (e.g., in whom an initial viralresponse (IVR) was observed), but in whom the therapeutic response wasnot maintained (referred to as “relapsers”). The previous therapygenerally can include treatment with IFN-α monotherapy, or IFN-αcombination therapy, where the IFN-α combination therapy may includeadministration of IFN-α and an antiviral agent such as ribavirin.

The terms “non-CIFN IFN-α therapy,” and “IFN-α therapy other than CIFN,”as used interchangeably herein in the context of previous IFN-α therapy,refer to any IFN-α-based therapy, other than therapy that includesadministration of CIFN, including IFN-α monotherapy and IFN-αcombination therapy (e.g., IFN-α and an antiviral such as ribavirin).

The terms “non-CIFN IFN-α” and “IFN-α other than CIFN,” usedinterchangeably herein, refer to IFN-α that is not consensus CIFN andincludes, but is not limited to, IFN-α2a; IFN-α2b; IFN-α2C; recombinantforms of naturally-occurring IFN-α, mixtures of naturally occurringIFN-α (e.g., IFN-αn1 and IFN-αn3); and derivatives, e.g., PEGylatedderivatives, of the foregoing. The term specifically excludes consensusIFN-α, as defined below.

The term “consensus IFN-α” (used interchangeably herein with “CIFN” and“IFN-alpha con”), as used herein refers specifically to a syntheticinterferons including IFN-con₁, IFN-con₂, IFN-con₃, and derivativesthereof, e.g., PEGylated derivatives. PEGylated derivatives of CIFN canbe produced according to methods in the art (see, e.g., U.S. Pat. Nos.5,985,265; 5,382,657; 5,559,213; and 6,177,074).

The term “early viral response,” used interchangeably with “initialviral response” (“IVR”) refers to the drop in viral titer within about24 hours, about 48 hours, about 2 days, or about 1 week after thebeginning of treatment for HCV infection.

The term “sustained viral response” (SVR; also referred to as a“sustained response” or a “durable response”), as used herein, refers tothe response of an individual to a treatment regimen for HCV infection,in terms of serum HCV titer. Generally, a “sustained viral response”refers to no detectable HCV RNA (e.g., less than about 500, less thanabout 200, or less than about 100 genome copies per milliliter serum)found in the patient's serum for a period of at least about one month,at least about two months, at least about three months, at least aboutfour months, at least about five months, or at least about six monthsfollowing cessation of treatment.

As used herein, the terms “treatment,” “treating,” and the like, referto obtaining a desired pharmacologic and/or physiologic effect. Theeffect may be prophylactic in terms of completely or partiallypreventing a disease or symptom thereof and/or may be therapeutic interms of a partial or complete cure for a disease and/or adverse affectattributable to the disease. “Treatment,” as used herein, covers anytreatment of a disease in a mammal, particularly in a human, andincludes: (a) preventing the disease or a symptom of a disease fromoccurring in a subject which may be predisposed to the disease but hasnot yet been diagnosed as having it (e.g., including diseases that maybe associated with or caused by a primary disease (as in liver fibrosisthat can result in the context of chronic HCV infection); (b) inhibitingthe disease, i.e., arresting its development; and (c) relieving thedisease, i.e., causing regression of the disease.

The terms “individual,” “host,” “subject,” and “patient” are usedinterchangeably herein, and refer to a mammal, including, but notlimited to, primates, including simians and humans, with humans being ofparticular interest.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “adose” includes a plurality of such doses and reference to “the method”includes reference to one or more methods and equivalents thereof knownto those skilled in the art, and so forth.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods of treating hepatitis C virus(HCV) infection in individuals having an HCV infection and have failedtreatment, e.g., individuals who have failed to respond to IFN-α therapyother than consensus interferon (CIFN) therapy; or who, during orfollowing cessation of IFN-α therapy other than CIFN therapy, havesuffered a relapse. The methods generally involve administration of CIFNand an antiviral agent such as ribavirin as follows: 1) administering afirst dosing regimen of CIFN, optionally with a dosing regimen ofribavirin; 2) followed by a second dosing regimen of CIFN and a dosingregimen of ribavirin. The lowest average daily serum concentration ofCIFN achieved by the first dosing regimen is higher than the highestaverage daily serum concentration of CIFN achieved by the second dosingregimen. The first and second dosing regimen of ribavirin may be thesame or different.

The first dosing regimen of CIFN (also referred to as “the inductionregimen”) generally involves administration of CIFN at about 9 μg, about15 μg, about 18 μg, or about 27 μg. The first dosing regimen canencompass a single dosing event, or at least two or more dosing events.

The first dosing regimen of CIFN can be administered daily, every otherday, three times a week, or substantially continuously so as to achievea desired average daily serum concentration of CIFN.

The first dosing regimen of CIFN (which may be administered incombination with an antiviral such as ribavirin) is administered for afirst period of time, which time period can be at least about 4 weeks,at least about 8 weeks, or at least about 12 weeks.

The first dosing regimen of CIFN (optionally administered withribavirin) is effective to reduce viral titer to a low viral titer,e.g., a reduction of at least about 0.5 log, at least about 1.0 log, atleast about 1.5 log, at least about 2.0 log, at least about 2.5 log, atleast about 3.0 log, at least about 3.5 log, at least about 4.0 log, atleast about 4.5 log, or at least about 5 log, compared to thepre-treatment viral titer, is achieved by the end of the first dosingregimen.

The second dosing regimen of CIFN (also referred to as “the maintenancedose”) generally involves administration of at least about 3 μg, atleast about 9 μg, at least about 15 μg, or at least about 18 μg of CIFN.The second dosing regimen can encompass a single dosing event, or atleast two or more dosing events.

The second dosing regimen of CIFN can be administered daily, every otherday, three times a week, or substantially continuously so as to achievea desired average daily serum concentration of CIFN.

The second dosing regimen of CIFN (in combination with ribavirin) iseffective to reduce viral titer still further, e.g., to undetectablelevels, e.g., to from about 500 genome copies per ml serum, to less thanor about 200 genome copies per ml serum, or to less than or about 100genome copies per ml serum.

The second dosing regimen of CIFN is administered for at least about 8weeks, at least about 12 weeks, at least about 20 weeks, at least about24 weeks, or at least about 48 weeks.

The treatment regimen described above (i.e., the first and second dosingregimens) effects a durable response (also referred to as a “sustainedresponse”), e.g., no detectable HCV RNA is found in the patient's serumfor a period of at least about one month, at least about two months, atleast about three months, at least about four months, at least aboutfive months, or at least about six months following cessation of atreatment regimen as described herein.

CIFN is administered in combination with an antiviral agent. Theantiviral agent can be administered simultaneously in separateformulations; simultaneously in the same formulation; administered inseparate formulations and within about 48 hours, within about 36 hours,within about 24 hours, within about 16 hours, within about 12 hours,within about 8 hours, within about 4 hours, within about 2 hours, withinabout 1 hour, within about 30 minutes, or within about 15 minutes orless. Where the CIFN and the antiviral agent are delivered as separateformulations, the CIFN and the antiviral agent may be delivered by thesame or different routes. The antiviral agent may be delivered in thesame or different dosing regimen as the CIFN.

In one embodiment, patients are treated with a combination of CIFN andribavirin. Ribavirin,1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, available from ICNPharmaceuticals, Inc., Costa Mesa, Calif., is described in the MerckIndex, compound No. 8199, Eleventh Edition. Its manufacture andformulation is described in U.S. Pat. No. 4,211,771. The invention alsocontemplates use of derivatives of ribavirin (see, e.g., U.S. Pat. No.6,277,830). The ribavirin may be administered orally in capsule ortablet form, or in the same or different administration form and in thesame or different route as the CIFN. Of course, other types ofadministration of both medicaments, as they become available arecontemplated, such as by nasal spray, transdermally, by suppository, bysustained release dosage form, etc. Any form of administration will workso long as the proper dosages are delivered without destroying theactive ingredient.

Ribavirin is generally administered in an amount ranging from about 30mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mgto about 200 mg, from about 200 mg to about 300 gm, from about 300 mg toabout 400 mg, from about 400 mg to about 1200 mg, from about 600 mg toabout 1000 mg, or from about 700 to about 900 mg per day.

In some embodiments, ribavirin is administered throughout the entirecourse of CIFN therapy. Ribavirin is administered with at least the lastdosing regimen, and may be administered with the last dosing regimen andany additional dosing regimen within the treatment regimen continuouswith the last dosing regimen. For example, where the treatment regimenincludes four dosing events, ribavirin is administered with the fourthdose, and may optionally be administered with the third and fourthdoses, the second, third, and fourth doses, or with the first, second,third and fourth doses.

Exemplary, non-limiting treatment regimens include the following.

Treatment Regimen 1A: 15 μg CIFN/day for eight weeks, followed by 9 μgCIFN/day for 16 weeks to 40 weeks. Ribavirin is administered 1000-1200mg per day throughout the treatment regimen.

Treatment Regimen 1B: 15 μg CIFN/day for eight weeks, followed by 9 μgCIFN/day for 16 weeks to 40 weeks. Ribavirin is administered 1000-1200mg per day for the last 16-40 weeks.

Treatment Regimen 2A: 15 μg CIFN/day for eight weeks, followed by 15 μgCIFN three times per week (TIW) for 16-40 weeks. Ribavirin isadministered 1000-1200 mg per day throughout the treatment regimen.

Treatment Regimen 2B: 15 μg CIFN/day for eight weeks, followed by 15 μgCIFN three times per week (TIW) for 16-40 weeks. Ribavirin isadministered 1000-1200 mg per day for the last 16-40 weeks.

Treatment Regimen 3A: 27 μg CIFN/day for four weeks, followed by 18 μgCIFN/day for eight weeks, followed by 9 μg CIFN day for 12 weeks,followed by 9 μg CIFN TIW for 24 weeks. Ribavirin is administered1000-1200 mg per day throughout the treatment regimen.

Treatment Regimen 3B: 27 μg CIFN/day for four weeks, followed by 18 μgCIFN/day for eight weeks, followed by 9 μg CIFN day for 12 weeks,followed by 9 μg CIFN TIW for 24 weeks Ribavirin is administered1000-1200 mg per clay beginning with the eight week course of 18 μgCIFN/day and continued for the remainder of the treatment regimen.

Treatment Regimen 3C: 27 μg CIFN/day for four weeks, followed by 18 μgCIFN/day for eight weeks, followed by 9 μg CIFN/day for 12 weeks,followed by 9 μg CIFN TIW for 24 weeks Ribavirin is administered1000-1200 mg per day beginning with the 12 week course of 9 μg CIFN/dayand continued for the remainder of the treatment regimen.

Treatment Regimen 3D: 27 μg CIFN/day for four weeks, followed by 18 μgCIFN/day for eight weeks, followed by 9 μg CIFN day for 12 weeks,followed by 9 μg CIFN TIW for 24 weeks Ribavirin is administered1000-1200 mg per day beginning with the 24 week course of 9 μg CIFN/TIWand continued for the remainder of the treatment regimen.

Treatment Regimen 4A: 18 μg CIFN/day for four weeks, followed by 9 μgCIFN/day for 20 weeks, followed by 9 μg CIFN TIW for 24 weeks. Ribavirinis administered 1000-1200 mg per day throughout the treatment regimen.

Treatment Regimen 4B: 18 μg CIFN/day for four weeks, followed by 9 μgCIFN/day for 20 weeks, followed by 9 μg CIFN TIW for 24 weeks. Ribavirinis administered 1000-1200 mg per day beginning with the 20 week courseof 9 μg CIFN/day and continued throughout the treatment regimen.

Treatment Regimen 4C: 18 μg CIFN/day for four weeks, followed by 9 μgCIFN/day for 20 weeks, followed by 9 μg CIFN TIW for 24 weeks. Ribavirinis administered 1000-1200 mg per day beginning with the 24 week courseof 9 μg CIFN TIW and continued throughout the treatment regimen.

Treatment Regimen 5A: 9 μg CIFN/day for 8-12 weeks, followed by 9 μgCIFN three times a week for the balance of the treatment period (e.g.,36 to 40 weeks), wherein the treatment period is a total of 48 weeks.Ribavirin is administered 1000-1200 mg per day throughout the treatmentregimen.

Treatment Regimen 5B: 9 μg CIFN/day for 8-12 weeks, followed by 9 μgCIFN three times a week (TIW) for the balance of the treatment period(e.g., 36 to 40 weeks), wherein the treatment period is a total of 48weeks. Ribavirin is administered 1000-1200 mg per day beginning withadministration of the treatment course of 9 μg CIFN three times a weekand continued throughout the remainder of the treatment regimen.

Guidance for dosage regimens is found in the art. See, e.g., Kaiser etal. (Apr. 20, 2001) 36^(th) Annual Meeting of the European Associationfor the Study of the Liver, Prague; Sjögren (Apr. 20, 2001) 36^(th)Annual Meeting of the European Association for the Study of the Liver,Prague; Sjögren (Apr. 30, 2001) 35^(th) Annual Meeting of the EuropeanAssociation for the Study of the Liver, Rotterdam; and Balmon Melian andPlosker (2001) Drugs 61:1-31; and U.S. Pat. No. 5,980,884.

IFN-Alpha

The instant methods involve administering to a “treatment-failure”patient an amount of CIFN and ribavirin effective to reduce viral titerand to effect a sustained viral response. Treatment failure patientsinclude non-responders and relapsers who previously underwent treatmentwith IFN-α other than CIFN. Such previous treatments include treatmentwith non-CIFN IFN-α monotherapy, and non-CIFN IFN-α combination therapy(e.g., non-CIFN IFN-α plus ribavirin).

The term “non CIFN interferon-alpha” as used herein refers to IFN-αproteins, other than CIFN, that inhibit viral replication and cellularproliferation and modulate immune response. The term “non CIFNinterferon-alpha” includes: (1) any naturally occurring IFN-α; (2)recombinant interferon alpha-2b such as Intron-A interferon availablefrom Schering Corporation, Kenilworth, N.J.; (3) recombinant interferonalpha-2a such as Roferon interferon available from Hoffmann-La Roche,Nutley, N.J.; (4) recombinant interferon alpha-2C such as Berofor alpha2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc.,Ridgefield, Conn.; (5) interferon alpha-n1, a purified blend of naturalalpha interferons such as Sumiferon available from Sumitomo, Japan or asWellferon interferon alpha-n1 (INS) available from the Glaxo-WellcomeLtd., London, Great Britain; (6) interferon alpha-n3 a mixture ofnatural alpha interferons made by Interferon Sciences and available fromthe Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.

The term “non-CIFN IFN-α” also encompasses derivatives of non-CIFN IFN-αthat are derivatized to alter certain properties such as serumhalf-life. As such, the term “non-CIFN IFN-α” includes glycosylatednon-CIFN IFN-α; non-CIFN IFN-α derivatized with polyethylene glycol(“PEGylated IFN-α”); and the like. PEGylated IFN-α, and methods formaking same, are discussed in, e.g., U.S. Pat. Nos. 5,382,657;5,981,709; 5,824,784; 5,985,265; and 5,951,974. PEGylated IFN-αencompasses conjugates of PEG and any of the above-described IFN-αmolecules, including, but not limited to, PEG conjugated to interferonalpha-2a (Roferon, Hoffman La-Roche, Nutley, N.J.), interferon alpha 2b(Intron, Schering-Plough, Madison, N.J.), interferon alpha-2c (BeroforAlpha, Boehringer Ingelheim, Ingelheim, Germany).

The term “consensus IFN-α” (also referred to as “CIFN” and “IFN-con”)includes CIFN such as those described in U.S. Pat. Nos. 4,897,471 and4,695,623 (e.g., Examples 7, 8 or 9 thereof) and the specific productavailable from Amgen, Inc., (Infergen®, Amgen, Thousand Oaks, Calif.).The term encompasses but is not limited to the amino acid sequencesdesignated IFN-con₁, IFN-con₂ and IFN-con₃ which are disclosed in U.S.Pat. Nos. 4,695,623 and 4,897,471. DNA sequences encoding IFN-con can besynthesized as described in the aforementioned patents or other standardmethods.

Additional Therapeutic Agents

CIFN therapy according to the invention can be carried out inconjunction with therapy for diseases and disorders other than HCV thatan individual having an HCV may suffer from. Such diseases include humanimmunodeficiency virus (HIV) infection; disorders include disordersassociated with HIV infection, and include, but are not limited to,fungal infections, respiratory tract infections, infections of the eye,Kaposi's sarcoma, and the like.

CIFN can be administered together with (i.e., simultaneously in separateformulations; simultaneously in the same formulation; administered inseparate formulations and within about 48 hours, within about 36 hours,within about 24 hours, within about 16 hours, within about 12 hours,within about 8 hours, within about 4 hours, within about 2 hours, withinabout 1 hour, within about 30 minutes, or within about 15 minutes orless) one or more additional therapeutic agents. Therapeutic agents thatcan be administered in combination therapy include, but are not limitedto, anti-inflammatory, anti-viral, anti-fungal, anti-mycobacterial,antibiotic, amoebicidal, trichomonocidal, analgesic, anti-neoplastic,anti-hypertensives, anti-microbial and/or steroid drugs.

In some embodiments, patients are treated with a combination of IFN-αand one or more of the following; beta-lactam antibiotics,tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin,sulfonamides, nitrofurazone, nalidixic acid, cortisone, hydrocortisone,betamethasone, dexamethasone, fluocortolone, prednisolone,triamcinolone, indomethacin, sulindac, acyclovir, amantadine,rimantadine, recombinant soluble CD4 (rsCD4), anti-receptor antibodies(e.g., for rhinoviruses), nevirapine, cidofovir (Vistide™), trisodiumphosphonoformate (Foscarnet™), famcyclovir, pencyclovir, valacyclovir,nucleic acid/replication inhibitors, zidovudine (AZT, Retrovir™),didanosine (dideoxyinosine, ddI, Videx™), stavudine (d4T, Zerit™),zalcitabine (dideoxycytosine, ddC, Hivid™), nevirapine (Viramune™),lamivudine (Epivir™, 3TC), protease inhibitors, saquinavir (Invirase™,Fortovase™), ritonavir (Norvir™), nelfinavir (Viracept™), efavirenz(Sustiva™), abacavir (Ziagen™), amprenavir (Agenerase™) indinavir(Crixivan™), ganciclovir, AzDU, delavirdine (Rescriptor™), kaletra,trizivir, rifampin, clathiromycin, erythropoietin, colony stimulatingfactors (G-CSF and GM-CSF), non-nucleoside reverse transcriptaseinhibitors, nucleoside inhibitors, adriamycin, fluorouracil,methotrexate, asparaginase and combinations thereof.

Formulations and Routes of Administration

CIFN and ribavirin are generally administered to individuals in aformulation (e.g., in the same or in separate formulations) with apharmaceutically acceptable excipient(s). A wide variety ofpharmaceutically acceptable excipients are known in the art and need notbe discussed in detail herein. Pharmaceutically acceptable excipientshave been amply described in a variety of publications, including, forexample, A. Gennaro (2000) “Remington: The Science and Practice ofPharmacy”, 20th edition, Lippincott, Williams, & Wilkins; PharmaceuticalDosage Forms and Drug Delivery Systems (1999) H. C. Ansel et al., eds7^(th) ed., Lippincott, Williams, & Wilkins; and Handbook ofPharmaceutical Excipients (2000) A. H. Kibbe et al., eds., 3^(rd) ed.Amer. Pharmaceutical Assoc.

The therapeutic agents CIFN and ribavirin, as well as additionaltherapeutic agents as described herein for combination therapies, can beadministered orally, subcutaneously, intramuscularly, parenterally, orother route. CIFN and ribavirin may be administered by the same route ofadministration or by different routes of administration. The therapeuticagents can be administered by any suitable means including, but notlimited to, for example, oral, rectal, nasal, topical (includingtransdermal, aerosol, buccal and sublingual), vaginal, parenteral(including subcutaneous, intramuscular, intravenous and intradermal),intravesical or injection into an affected organ.

The therapeutic agent(s) may administered in a unit dosage form and maybe prepared by any methods well known in the art. Such methods includecombining the compounds of the present invention with a pharmaceuticallyacceptable carrier or diluent which constitutes one or more accessoryingredients. A pharmaceutically acceptable carrier is selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice. Each carrier must be “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the subject. This carrier can be a solid or liquidand the type is generally chosen based on the type of administrationbeing used.

Examples of suitable solid carriers include lactose, sucrose, gelatin,agar and bulk powders. Examples of suitable liquid carriers includewater, pharmaceutically acceptable fats and oils, alcohols or otherorganic solvents, including esters, emulsions, syrups or elixirs,suspensions, solutions and/or suspensions, and solution and orsuspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules. Suchliquid carriers may contain, for example, suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, thickeners, and melting agents. Preferred carriers areedible oils, for example, corn or canola oils. Polyethylene glycols,e.g. PEG, are also good carriers.

Any drug delivery device or system that provides for the dosing regimenof the instant invention can be used. A wide variety of delivery devicesand systems are known to those skilled in the art.

Determining Effectiveness of Treatment

Whether a subject method is effective in treating an HCV infection canbe determined by measuring viral load, or by measuring a parameterassociated with HCV infection, including, but not limited to, liverfibrosis.

Viral load can be measured by measuring the titer or level of virus inserum. These methods include, but are not limited to, a quantitativepolymerase chain reaction (PCR) and a branched DNA (bDNA) test.Quantitative assays for measuring the viral load (titer) of HCV RNA havebeen developed. Many such assays are available commercially, including aquantitative reverse transcription PCR (RT-PCR) (Amplicor HCV Monitor™,Roche Molecular Systems, N.J.); and a branched DNA (deoxyribonucleicacid) signal amplification assay (Quantiplex™ HCV RNA Assay (bDNA),Chiron Corp., Emeryville, Calif.). See, e.g., Gretch et al. (1995) Ann.Intern. Med. 123:321-329.

Another method of determining viral load is by measuring the level ofserum antibody to HCV. Methods of measuring serum antibody to HCV arestandard in the art and include enzyme immunoassays, and recombinantinmmunoblot assays, both of which involve detection of antibody to HCVby contacting a serum sample with one or more HCV antigens, anddetecting any antibody binding to the HCV antigens using an enzymelabeled secondary antibody (e.g., goat anti-human IgG). See, e.g., Weisset al. (1995) Mayo Clin. Proc. 70:296-297; and Gretch (1997) Hepatology26:43S-47S.

While viral titers are the most important indicators of effectiveness ofa dosing regimen, other parameters can also be measured as secondaryindications of effectiveness. Secondary parameters include reduction ofliver fibrosis; and reduction in serum levels of particular proteins, asdescribed below.

Liver fibrosis reduction is determined by analyzing a liver biopsysample. An analysis of a liver biopsy comprises assessments of two majorcomponents: necroinflammation assessed by “grade” as a measure of theseverity and ongoing disease activity, and the lesions of fibrosis andparenchymal or vascular remodeling as assessed by “stage” as beingreflective of long-term disease progression. See, e.g., Brunt (2000)Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based onanalysis of the liver biopsy, a score is assigned. A number ofstandardized scoring systems exist which provide a quantitativeassessment of the degree and severity of fibrosis. These include theMETAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

Serum markers of liver fibrosis can also be measured as an indication ofthe efficacy of a subject treatment method. Serum markers of liverfibrosis include, but are not limited to, hyaluronate, N-terminalprocollagen III peptide, 7S domain of type IV collagen, C-terminalprocollagen I peptide, and laminin. Additional biochemical markers ofliver fibrosis include α-2-macroglobulin, haptoglobin, gamma globulin,apolipoprotein A, and gamma glutamyl transpeptidase.

Another secondary indicator of effectiveness of a treatment regimen isserum levels of serum alanine aminotransferase (ALT). Serum ALT levelsare measured, using standard assays. In general, an ALT level of lessthan about 80, less than about 60, less than about 50, or about 40international units per liter of serum is considered normal. In someembodiments, an effective amount of IFNα is an amount effective toreduce ALT levels to less than about 200 IU, less than about 150 IU,less than about 125 IU, less than about 100 IU, less than about 90 IU,less than about 80 IU, less than about 60 IU, or less than about 40 IU.

SUBJECTS SUITABLE FOR TREATMENT

Individuals who have been clinically diagnosed as infected with HCV aresuitable for treatment with the methods of the instant invention.Individuals who are infected with HCV are identified as having HCV RNAin their blood, and/or having anti-HCV antibody in their serum. Suchindividuals include anti-HCV ELISA-positive individuals, and individualswith a positive recombinant immunoblot assay (RIBA). Such individualsmay also, but need not, have elevated serum ALT levels.

Patients for whom the therapy of the invention is of particular benefitinclude treatment failure patients, which include patients who failed torespond to previous HCV therapy (referred to as “non-responders”) or whoinitially responded to previous therapy, but in whom the therapeuticresponse was not maintained (referred to as “relapsers”). The previoustherapy generally can include treatment with IFN-α monotherapy or IFN-αcombination therapy, where the combination therapy may includeadministration of IFN-α and an antiviral agent such as ribavirin. Asnon-limiting examples, individuals may have an HCV titer of at leastabout 10⁵, at least about 5×10⁵, or at least about 10⁶, genome copies ofHCV per milliliter of serum.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A method for treating a hepatitis C virus infection in an individual,the method comprising administering consensus interferon-α (CIFN) andribavirin, wherein CIFN is administered in a therapeutic regimencomprising a first dosing regimen of CIFN, followed by a second dosingregimen of CIFN, wherein the lowest average daily serum concentration ofCIFN achieved by the first dosing regimen is greater than the highestaverage daily serum concentration of CIFN achieved by the second dosingregimen, and wherein the individual treated has failed previousIFN-α-based therapy other than CIFN therapy.
 2. The method of claim 1,wherein ribavirin is administered during administration of at least thelast dosing event of the second dosing regimen.
 3. The method of claim2, wherein ribavirin is administered with additional dosing eventscontinuous with the last dosing event during which ribavirin isadministered.
 4. The method of any one of claims 1-3, wherein theindividual failed to respond to previous IFN-α-based therapy other thanCIFN therapy.
 5. The method of any one of claims 1-3, wherein theindividual has suffered a relapse following cessation of IFN-α therapyother than CIFN therapy.
 6. The method of claim 1, wherein the firstdosing regimen comprises administering 15 μg CIFN per day for eightweeks, wherein the second dosing regimen comprises administering 9 μgCIFN per day for a period of 16 to 40 weeks, and wherein ribavirin isadministered at 1000 to 1200 mg per day throughout the therapeuticregimen.
 7. The method of claim 1, wherein the first dosing regimencomprises administering 15 μg CIFN per day for eight weeks, wherein thesecond dosing regimen comprises administering 9 μg CIFN three times perweek for 16 to 40 weeks, and wherein ribavirin is administered at 1000to 1200 mg per day throughout the therapeutic regimen.
 8. The method ofclaim 1, wherein the first dosing regimen comprises administering 15 μgCIFN per day for eight weeks, wherein the second dosing regimencomprises administering 15 μg CIFN three times per week for 16 to 40weeks, and wherein ribavirin is administered at 1000 to 1200 mg per daythroughout the therapeutic regimen.
 9. The method of claim 1, whereinthe first dosing regimen comprises administering 15 μg CIFN per day foreight weeks, wherein the second dosing regimen comprises administering15 μg CIFN three times per week for 16 to 40 weeks, and whereinribavirin is administered at 1000 to 1200 mg per day during the seconddosing regimen.
 10. The method of claim 1, wherein the first dosingregimen comprises administering 27 μg CIFN per day for four weeksfollowed by administering 18 μg CIFN per day for eight weeks, whereinthe second dosing regimen comprises administering 9 μg CIFN per day for12 weeks followed by administering 9 μg CIFN three times per week for 24weeks, and wherein ribavirin is administered at 1000 to 1200 mg per daythroughout the therapeutic regimen.
 11. The method of claim 1, whereinthe first dosing regimen comprises administering 27 μg CIFN per day forfour weeks followed by administering 18 μg CIFN per day for eight weeks,wherein the second dosing regimen comprises administering 9 μg CIFN perday for 12 weeks followed by administering 9 μg CIFN three times perweek for 24 weeks, and wherein ribavirin is administered at 1000 to 1200mg per day beginning with the eight-week course of 18 μg CIFN per dayand continuing ribavirin administration for the remainder of thetherapeutic regimen.
 12. The method of claim 1, wherein the first dosingregimen comprises administering 27 μg CIFN per day for four weeksfollowed by administering 18 μg CIFN per day for eight weeks, whereinthe second dosing regimen comprises administering 9 μg CIFN per day for12 weeks followed by administering 9 μg CIFN three times per week for 24weeks, and wherein ribavirin is administered at 1000 to 1200 mg per daybeginning with the 12-week course of 9 μg CIFN per day and continuingribavirin administration for the remainder of the therapeutic regimen.13. The method of claim 1, wherein the first dosing regimen comprisesadministering 27 μg CIFN per day for four weeks followed byadministering 18 μg CIFN per day for eight weeks, wherein the seconddosing regimen comprises administering 9 μg CIFN per day for 12 weeksfollowed by administering 9 μg CIFN three times per week for 24 weeks,and wherein ribavirin is administered at 1000 to 1200 mg per daybeginning with the 24-week course of 9 μg CIFN three times per week andcontinuing ribavirin administration for the remainder of the therapeuticregimen.
 14. The method of claim 1, wherein the first dosing regimencomprises administering 18 μg CIFN per day for four weeks, wherein thesecond dosing regimen comprises administering 9 μg CIFN per day for 20weeks followed by administering 9 μg CIFN three times per week for 24weeks, and wherein ribavirin is administered at 1000 to 1200 mg per daythroughout the therapeutic regimen.
 15. The method of claim 1, whereinthe first dosing regimen comprises administering 18 μg CIFN per day forfour weeks, wherein the second dosing regimen comprises administering 9μg CIFN per day for 20 weeks followed by administering 9 μg CIFN threetimes per week for 24 weeks, and wherein ribavirin is administered at1000 to 1200 mg per day beginning with the 20-week course of 9 μg CIFNper day and continuing ribavirin administration for the remainder of thetherapeutic regimen.
 16. The method of claim 1, wherein the first dosingregimen comprises administering 18 μg CIFN per day for four weeks,wherein the second dosing regimen comprises administering 9 μg CIFN perday for 20 weeks followed by administering 9 μg CIFN three times perweek for 24 weeks, and wherein ribavirin is administered at 1000 to 1200mg per day beginning with the 24-week course of 9 μg CIFN three timesper week and continuing ribavirin administration for the remainder ofthe therapeutic regimen.
 17. The method of claim 1, wherein the firstdosing regimen comprises administering 9 μg CIFN per day for 8 to 12weeks, wherein the second dosing regimen comprises administering 9 μgCIFN three times per week for 36 to 40 weeks, and wherein ribavirin isadministered at 1000 to 1200 mg per day throughout the therapeuticregimen.
 18. The method of claim 1, wherein the first dosing regimencomprises administering 9 μg CIFN per day for 8 to 12 weeks, wherein thesecond dosing regimen comprises administering 9 μg CIFN three times perweek for 36 to 40 weeks, and wherein ribavirin is administered at 1000to 1200 mg per day throughout the second dosing regimen.
 19. The methodof claim 1, wherein the therapeutic regimen achieves a sustained viralresponse.